Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

• the invention relates to aryloxyalkylpyrazoles, to the preparation thereof and to compositions and methods for the use thereof as antiviral agents.
• the invention relates to 4-(aryloxyalkyl)pyrazoles and pharmaceutically acceptable acid-addition salts thereof, said pyrazoles having the formula ##STR4## wherein Ar is phenyl or substituted phenyl, Alk is an alkylene bridge, and R, R' and R" are selected substituents as defined hereinbelow.
• the invention relates to phenylenedioxy compounds of the formulas ##STR5## wherein R is hydrogen or lower-alkyl, R' is lower-alkyl and n is an integer from 3 to 7; and acid-addition salts of said compounds.
• the invention relates to a composition for combatting viruses which comprises an antivirally effective amount of a compound of formula I, II or III in admixture with a suitable carrier or diluent.
• the invention relates to a process for preparing a compound of formula I which comprises reacting a diketone of the formula Ar-O-Alk-CH(COR')COR" with a hydrazine of the formula H 2 NNHR.
• the invention relates to a process for preparing a compound of formula II or III which comprises reacting a bis-diketone of the formula ##STR6## with a hydrazine of the formula H 2 NNHR.
• the invention in a further process aspect, relates to a method for combatting viruses which comprises contacting the locus of said viruses with an antivirally effective amount of at least one compound of formula I, II or III.
• a preferred aspect of the invention relates to compounds of formula I above wherein R is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, carboalkoxyalkyl of 3 to 6 carbon atoms, or phenyl; R' is alkyl of 1 to 4 carbon atoms or phenyl; R" is alkyl of 1 to 4 carbon atoms, phenyl or hydroxy; Alk is alkylene of 3 to 10 carbon atoms optionally interrupted by an oxygen atom separated by at least two carbon atoms from the terminal bonds of Alk; and Ar is phenyl or phenyl substituted by from 1 to 3 substituents selected from the group consisting of halo, hydroxy, nitro, alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, hydroxyalkyl of 2 to 4 carbon atoms, benzyloxy and trifluoro
• Particularly preferred aspects of the invention relate to compounds of formula I wherein R is hydrogen, and R' and R" are alkyl of 1 to 4 carbon atoms; wherein R is hydrogen, R' and R" are alkyl of 1 to 4 carbon atoms, and Ar is 2-chloro-4-methoxyphenyl; wherein R is hydrogen, and R' and R" are phenyl; wherein R is lower-alkyl of 1 to 6 carbon atoms, and R' and R" are alkyl of 1 to 4 carbon atoms; or wherein R is lower-alkyl of 1 to 6 carbon atoms, R' and R" are alkyl of 1 to 4 carbon atoms and Ar is 2-chloro-4-methoxyphenyl.
• Alk stands for a saturated aliphatic hydrocarbon bridge containing from 3 to 10 carbon atoms.
• the alkylene bridge may be straight or branched.
• a preferred class of compounds are those where Alk is straight chain alkylene of 3 to 10 carbon atoms, and if the Alk bridge is branched, it is preferred that it be symmetrical, that is with the branching at the same relative positions from either end of the bridge.
• the alkylene bridge, Alk is optionally interrupted by an oxygen atom separated by at least two carbon atoms from the terminal bonds of Alk.
• the oxygen atom is preferably in the center of the alkylene bridge, equidistant from the terminal bonds of Alk.
• the carbon chains of R and R' can be straight or branched, thus including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl and tertiary-butyl.
• halo substituents When two or three monovalent substituents are present on the phenyl ring of Ar, they can be the same or different. When halo substituents are present, they can be any of the four common halogens, fluoro, chloro, bromo or iodo.
• the compounds of formula I are prepared by interacting a diketone or keto-ester of the formula ##STR7## wherein R' is lower-alkyl and R" is lower-alkyl or lower-alkoxy, with hydrazine or a derivative thereof of the formula H 2 NNHR.
• the intermediate diketones and keto-esters are obtained as described in copending application Ser. No. 576,311, filed May 12, 1975, now U.S. Pat. No. 4,031,246, issued June 21, 1977, the disclosure of which is incorporated herein by reference.
• the reaction is carried out by heating the reactants together, preferably at a temperature between about 50° and 100° C. in an inert solvent for a period ranging from several minutes to several hours. Stoichiometrically equivalent amounts of the reactants may be used, although a slight excess of hydrazine reactant is generally employed.
• a further aspect of the invention relates to compounds of formulas II or III, given above, wherein R is hydrogen or lower-alkyl of 1 to 6 carbon atoms; R' is alkyl of 1 to 4 carbon atoms; and n is an integer from 3 to 7.
• the compounds of formulas II and III are prepared by interacting a compound of formula IV, given above, with hydrazine or a derivative thereof of the formula H 2 NNHR. Substantially equimolar quantities of bis-diketone IV and hydrazine give a monopyrazole of formula II. The use of two or more molecular equivalents of hydrazine relative to the bis-diketone produces a bispyrazole of formula III.
• the reaction conditions are essentially the same as those used to prepare compounds of formula I.
• the intermediate bis-diketones (IV) are in turn prepared by one of two methods (a) or (b), as follows:
• acid-addition salts of the compounds of the invention are prepared and used, the nature of the anion is not critical provided it is relatively non-toxic to mammals and thus pharmaceutically acceptable.
• Such anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate and other alkanoates such as hexanoate and nonanoate; lactate, tartrate, cyclohexylsulfamate and various sulfonates such as methanesulfonate, tosylate and naphthalenesulfonate.
• the structures of the compounds of the invention were established by the modes of synthesis, by elementary analysis, and by infrared and nuclear magnetic resonance spectral determinations.
• Biological evaluation of the compounds of the invention has shown that they possess antiviral activity. They are thus useful in combatting viruses present on inanimate surfaces as well as viral infections in animal organisms.
• the in vitro testing of the compounds of the invention against herpes simplex viruses types 1 and 2 and rhinovirus 14 has showed that they inhibited viral growth at minimum concentrations (MIC) ranging from about 0.7 to about 50 micrograms per milliliter. The MIC values were determined by standard serial dilution procedures. In vivo activity has also been demonstrated in the treatment of mouse genital herpes simplex type 2 infection.
• the antiviral compositions are formulated by preparing a dilute solution or suspension in an organic or aqueous-organic medium, for example ethyl alcohol, acetone, dimethylsulfoxide, and the like; and are applied to the locus to be disinfected by conventional means such as spraying, swabbing or immersing.
• the compounds can be formulated as ointments or creams by incorporating them in conventional ointment or cream bases, such as alkylpolyether alcohols, cetyl alcohol, stearyl alcohol and the like; as jellies by incorporating them in conventional jelly bases such as glycerin and tragacanth; or as aerosol sprays or foams.
• the antivirally effective component of the composition is present in a conventration of between about 0.7 parts per million and about 5 percent by weight, depending upon the chemical species used, the object to be treated and the type of formulation employed.
• concentrations in the lower part of the range are effective.
• concentrations in the upper part of the range are preferred.
• herpes simplex type 1 herpes 1
• herpes simplex type 2 herpes simplex type 2
• human rhinovirus type 14 showed antiviral activity at minimal inhibitory concentrations (MIC) of 3-6, 6 and 3 micrograms per milliliter, respectively.
• MIC minimal inhibitory concentrations
• the compound was also effective in treatment of mice vaginally infected with herpes simplex type 2; survival rates of 80-100% were observed after intravaginal administration of a 10% aqueous solution of the compound in saturated cotton tampons.
• Ar is 2-Cl-4-CH 3 OC 6 H 3
• Alk is (CH 2 ) 6
• R is COCH 2 CH 2 CH 2 N(CH 2 ) 4 O
• R' and R" are C 2 H 5 ].
• 1-methylpyrazole derivatives can be prepared, namely, 4- ⁇ 6-[4-(4,4-dipropionylbutyloxy)phenoxy]propyl ⁇ -3,5-diethyl-1-methylpyrazole [II; R is CH 3 , R' is C 2 H 5 , n is 3] and 4,4'-(1,4-phenylenedioxy)bis(4,1-butanediyl)bis[3,5-diethyl-1H-pyrazole] [III; R is CH 3 , R' is C 2 H 5 , n is 3].

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• Chemical & Material Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Virology (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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Cited By (14)

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Citations (4)

• 1977
  • 1977-08-05 US US05/822,246 patent/US4171365A/en not_active Expired - Lifetime
• 1978
  • 1978-07-21 CA CA307,919A patent/CA1112244A/fr not_active Expired
  • 1978-07-24 IE IE1479/78A patent/IE47139B1/en unknown
  • 1978-07-25 NZ NZ187960A patent/NZ187960A/xx unknown
  • 1978-07-27 AU AU38397/78A patent/AU515984B2/en not_active Expired
  • 1978-07-31 GB GB7831733A patent/GB2003859B/en not_active Expired
  • 1978-08-03 IT IT26458/78A patent/IT1099591B/it active
  • 1978-08-03 NL NL787808179A patent/NL7808179A/xx not_active Application Discontinuation
  • 1978-08-04 BE BE789002A patent/BE869509A/fr not_active IP Right Cessation
  • 1978-08-04 FR FR7823184A patent/FR2409988A1/fr active Granted
  • 1978-08-04 DE DE19782834322 patent/DE2834322A1/de not_active Withdrawn
  • 1978-08-04 DK DK345778A patent/DK345778A/da not_active Application Discontinuation
  • 1978-08-04 SE SE7808418A patent/SE7808418L/xx unknown
  • 1978-08-04 CH CH831978A patent/CH635080A5/fr not_active IP Right Cessation
  • 1978-08-04 LU LU80078A patent/LU80078A1/fr unknown
  • 1978-08-05 JP JP9575878A patent/JPS5430175A/ja active Pending
• 1979
  • 1979-02-14 FR FR7903767A patent/FR2409989A1/fr active Granted

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